Resistance of neuronal nitric oxide synthase-deficient mice to cocaine-induced locomotor sensitization

Abstract

In brain, nitric oxide (NO) is considered as a retrograde messenger involved in synaptic plasticity. The present study was undertaken to investigate whether mice lacking the neuronal nitric oxide synthase (nNOS) gene are protected from cocaine-induced behavioral sensitization. Mice were administered, IP. either saline or cocaine (15 mg/kg) for 5 days. Sensitization was determined as an increase in cocaine-induced locomotor activity on day 5 compared with day 1 and an amplified response of cocaine-experienced mice to a challenge cocaine injection given after a 10-day drug free period (e.g., on day 15). To investigate the development of a context-dependent locomotion (conditioning), the responses of cocaine- and saline-experienced mice to a saline injection were determined on day 17. Male homozygote nNOS(-/-) mice were sensitive to the acute effect of cocaine (15 mg/kg) on day 1; however, they developed neither a sensitized response to cocaine (on day 5 and 15) nor a conditioned locomotion. Female homozygote nNOS(-/-) mice neither were responsive to 15 mg/kg cocaine on day 1,5 and 15, nor did they develop a conditioned locomotion. In contrast, the same cocaine regimen delivered to male and female heterozygote nNOS(+/-) mice, and wild type mice (B6 J/sv129, C57BL/6 and sv129) resulted in sensitization to cocaine-induced locomotor activity and context-dependent locomotion. Investigation of [3H]cocaine disposition in the striatum and frontal cortex of the mice revealed neither gender nor strain differences in the drug disposition. Also, no major difference in striatal dopaminergic markers between homozygote nNOS(-/-) and wild type mice was observed. The most significant distinction, however, was the finding that nNOS(-/-) mice are completely deficient in striatal nNOS binding sites. Taken together, our results suggest that the resistance of homozygote nNOS(-/-) mice to cocaine-induced behavioral sensitization is primarily due to the deletion of the nNOS gene. Considering the role of NO in synaptic plasticity, it is conceivable that reduced brain NOS activity blunts the processes that underlie the development of sensitization to cocaine.

Differential Effects of Amphetamines-Induced Neurotoxicity on Appetitive and Aversive Pavlovian Conditioning in Mice

“…Striatum (caudate putamen only), frontal cortex, hippocampus (dorsal and ventral), and amygdala were obtained by gross dissection and immediately frozen on dry ice. Routinely, tissue from one hemisphere was used for high-performance liquid chromatography (HPLC) combined with electrochemical detection for the determination of concentrations of DA, 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-HT, and 5-hydroxyindole acetic acid (5-HIAA) (Itzhak et al, 1998). Tissue from the other hemisphere was used to determine the density of DA transporter (DAT) and 5-HT transporter (5-HTT) binding sites by saturation binding assays using [ (Itzhak et al, 1998(Itzhak et al, , 2003a.…”

Methamphetamine and MDMA (Ecstasy) Neurotoxicity: 'of Mice and Men'

“…Second, selective neuronal nitric oxide synthase (nNOS) inhibitors such as 7-nitroindazole (7-NI), 3-bromo 7-nitroindazole and S-methylthiocitrulline blocked METHinduced dopaminergic neurotoxicity in mice with no effect on METH-induced hyperthermia (26,36). Third, mice deficient in the nNOS gene (nNOS knockout; KO) were resistant to METH-induced dopaminergic neurotoxicity compared to wild type mice (37).…”

The Neuronal Nitric Oxide Synthase Gene Is Critically Involved in Neurobehavioral Effects of Alcohol

“…Evidence from previous studies has implicated the nNOS-NO pathway in the modulation of CNSmediated drug effects. Thus, inhibition of NOS has been shown to influence the development of tolerance (Khanna et al, 1993(Khanna et al, , 1995Kolesnikov et al, 1993Kolesnikov et al, , 1997 and sensitization (Itzhak et al, 1998;Itzhak and Martin, 2000) to several drugs of abuse, including alcohol. Beside these findings, two other lines of evidence have prompted us to study the role of the nNOS gene in the regulation of neurobehavioral effects of alcohol:…”